Pancreatic cancer treatment presents one of the most challenges in clinical oncology as majority of the patients with advanced pancreatic cancer do not response to current available chemotherapeutic and radiotherapy and the prognosis of the patients is one of the worst among all cancer types. The objective of this proposed study aims at developing a multi-functional theranostic nanoparticle platform that combines demonstrated imaging capability and receptor specificity of the nanoparticles with novel designs for drug delivery to overcome physical and intrinsic barriers that confer drug resistance in pancreatic cancer. Our extensive research supported by NCI CCNE program led to the development of biodegradable and receptor targeted magnetic iron oxide nanoparticles (lONP) as a molecular imaging probe for MRI of pancreatic cancer. In this project, we will further develop a theranostic nanoparticle platform that combines MRI and drug delivery capabilities with special ability to overcome the barriers causing resistance to therapy in pancreatic cancer tissues and effectively deliver single or multiple therapeutic agents such as chemotherapy drugs and siRNA expressing DNA cassettes into the tumor cells (Aim 1). The drug-nanoparticle complex will be targeted to cellular receptors, such as urokinase plasminogen activator receptor, that are highly expressed in pancreatic cancer cells and active tumor stromal cells to facilitate the intratumoral delivery of the nanoparticles. We will develop novel MRI approaches that are designed and optimized for specific and sensitive detection of the theranostic magnetic nanoparticles in the pancreatic cancer lesions by MRI (Aim 2). We will determine the tumor targeted therapeutic effect, intratumoral distribution of the nanoparticles, and the imaging capability of monitoring response to therapy in orthotopic human pancreatic cancer xenograft and in a mouse transgenic tumor model using MRI and histological analysis of the tumor tissues (Aim 3 and Aim 4). To translate the theranostic magnetic nanoparticles into clinical applications, we will conduct biodistribution, systemic toxicity, and pharmacokinetic studies In normal and tumor bearing mouse models (Aim 5). The development of proposed theranostic nanoparticles that that are capable of targeted delivery of large amounts and multiple drugs into pancreatic cancer cells and tumor environment while providing imaging tools for monitoring drug delivery and response is particularly important for the effective treatment of pancreatic cancer since the cancer patients have a very short median survival time. RELEVANCE (See instructions); This research project will develop novel tumor targeted nanotechnology therapeutics for improving the treatment of pancreas cancer.